A growing number of diseases are associated with inappropriate depositions of protein aggregates, typically including neurological disorders and systemic amyloidoses.1 During malignancy, proteins are usually uncontrollably over-expressed or structurally affected due to genetic mutations, resulting in changes in activity and protein-protein interactions in cancer cells.2 A subset of neuroblastomas, carcinomas and myelomas show an abnolinal accumulation of tumor-suppressor p53 protein aggregates.51, 19 
The tumor-suppressor p53 is a key regulator of the cell cycle and is mutated in approximately 50% of reported human tumor cases, making it a major target for anticancer therapy.3 p53 is a transcription factor that acts as a homo-tetramer, with each monomer consisting of an N-terminal transactivation domain, a proline-rich domain, a central DNA-binding domain, a tetramerization domain and a C-terminal regulatory domain (FIG. 1). According to IARC TP53 Mutation Database,4 over 95% of the malignant mutations occur in the DNA-binding domain where they cluster in so-called hot-spots of mutation.
Previously, it has been shown that the DNA-binding domain of p53 is conformationally unstable and that the majority of hot-spot disease mutants such as R175H, R282W, R248Q and R249S further destabilize the DNA-binding domain5 (FIG. 1). Consequently, a proportion of these mutants are at least partially unfolded6 and, therefore, inactive. Hence, these mutants, present in about 30% of reported clinical cases,7 are usually referred to as “structural” mutants. A second class of disease mutants, such as R273H and R248W, which are present at the p53 DNA-binding interface, affect DNA binding without affecting the conformational stability of the domain, and are, therefore, referred to as “contact” mutants, representing about 20% of cases.
As native p53 functions as a tetrameric protein, it is generally accepted that the dominant-negative effect arises from the incorporation of both inactive mutant and wild-type p53 molecules into mixed tetramers, resulting in a reduced cellular concentration of functional p53.8 
Several biological mechanisms leading to gain of tumorigenic function of p53 mutants have been proposed,9 and one pivotal mechanism seems to be the ability of mutant p53 to interact with and attenuate the function of its paralogues p63 and p73, whose transactivating isoforms have been demonstrated to inhibit tumor metastasis and increase the sensitivity for radiochemotherapies.10, 11 
Since structural p53 mutants display a dominant gain-of-function phenotype, major effort has been invested in the development of therapeutic treatments that stabilize and, thus, reactivate mutant p53.52, 18 For instance, it has been shown that the introduction of N239Y as a secondary mutation in the p53C DNA-binding domain augments the stability of several, but not all, p53 cancer mutants. Although favorable, this would only functionally restore a limited number of mutants. Several screens have been performed in order to identify drugs that stabilize structural p53 mutants and reactivate its transcriptional activity; two such promising and structurally unrelated compounds are PRIMA-1 (p53 reactivation and induction of massive apoptosis) and MIRA-1 (mutant p53 reactivation and induction of rapid apoptosis). Another notorious drug is the CP-31398 molecule that was claimed to rescue mutant p53. Despite the therapeutic potency of strategies stabilizing structural p53 mutants, it is noted that, in murine models, prolonged treatment might favor the development of p53-resistant tumors or result in premature aging in some murine models.
Other therapeutic strategies do not focus on stabilizing mutant p53, but on increasing the level of active wild-type p53 in heterozygous p53 mutant cancer cells. This is achieved by manipulating cellular regulators of p53, mostly Mdm2. Mdm2 is a negative regulator of p53, inhibiting p53 through at least two mechanisms: binding to the transcriptional activation domain of p53, thereby preventing transcription, and by promoting p53 ubiquitination and ultimate degradation. The MDM2 gene itself is a transcriptional target of p53, generating a negative feedback loop when p53 activity increases. Several compounds have been identified that target the physical interaction between p53 and Mdm2; examples include the 3G5 antibody that competes for the p53 binding site of Mdm2,55 the microbial extract chlorofusin that binds Mdm256 and RITA (reactivation of p53 and induction of tumor cell apoptosis) that binds the N-terminus of p53 preventing its interaction with Mdm2.57 Probably the most prominent inhibitors of the p53-Mdm2 interaction are the nutlins (Roche).53, 54 The nutlins are small permeable compounds that bind to the p53 binding pocket of Mdm2 with IC50 values in the nanomolar range. Currently, they are being evaluated in early clinical trials.
A different approach to augment the level of active wild-type p53 in heterozygous p53 mutant cancer cell is the introduction of wild-type p53 by means of adenoviral vectors. This already resulted in the development of several commercial medicines, like ADVEXIN™ (Introgen) and GENDICINE™ (Sibiono), the first anticancer gene therapy drug. Onyx-15 (Onyx Pharmaceuticals) is also based on an adenoviral vector, but instead of supplementing the cells with wild-type p53, it will specifically kill mutant cancer cells. However, it should be remarked that adenovirus-based gene therapy has several draw-backs: it is not expressed for long-term, has a limited packaging capacity to express other genes, and it spreads slowly and works poorly when injected intravenously. But, more importantly, adenoviruses, even inactivated, can prompt an immune response, which already resulted in the death of a patient treated with adenovirus gene therapy.
An alternative strategy in p53 cancer therapy focuses on the p53 homologues p63 and p73. p53, p63 and p73 share strong structural similarity; nonetheless, there seems to be functional diversity. For instance, aberrancies in p63 and p73 cause severe developmental abnormalities but no increased cancer susceptibility like p53 mutants.58 Nevertheless, p63 and p73 regulate cell cycle and apoptosis just like p53 and their inactivation is thought to contribute to metastasis. Consequently, current data has shown that an isoform of p73 functions as a tumor suppressor.59 Mutant p53 interacts with p63 and p73 through the DNA-binding core domain.60 A drug that breaks this oncogenic complex liberating p63 and p73 constitutes a favorable scenario for cancer treatment. Accordingly, it has recently been shown that disruption of the mutant p53 and p73 complex by small peptides consequently restores p73 activity.61 Notwithstanding this potential, such a strategy is severely complicated by the occurrence of many isoforms of p63 and p73 and the residing unclearness about the exact role of p63 and p73 in tumor progression.
There is thus a need for alternative strategies to combat cancer, without any of the aforementioned problems.